The transmissible spongiform encephalopathies (TSE) constitute a group of neurodegenerative diseases. In humans these diseases include Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome, Fatal Familial Insomnia, and Kuru (see, e.g., Harrison's Principles of Internal Medicine, Isselbacher et al., eds., McGraw-Hill, Inc. New York, (1994); Medori et al. 1992 N. Engl. J. Med., 326: 444-9.). In animals the TSE's include sheep scrapie, bovine spongiform encephalopathy, transmissible mink encephalopathy, and chronic wasting disease of captive mule deer and elk (Gajdusek, (1990) Subacute Spongiform Encephalopathies: Transmissible Cerebral Amyloidoses Caused by Unconventional Viruses. Pp. 2289-2324 In: Virology, Fields, ed. New York: Raven Press, Ltd.). Transmissible spongiform encephalopathies are characterized by the same hallmarks: a spongiform degeneration, reactive gliosis in the cortical and subcortical gray matters of the brain, and transmission when experimentally inoculated into laboratory animals including primates, rodents, and transgenic mice.
Recently, the rapid spread of bovine spongiform encephalopathy and its correlation with elevated occurrence of spongiform encephalophathies in humans has lead to a significant increase of interest in the detection of transmissible spongiform encephalopathies in non-human mammals. The tragic consequences of accidental transmission of these diseases (see, e.g., Gajdusek, Infectious Amyloids, and Prusiner Prions In Fields Virology. Fields, et al., eds. Lippincott-Ravin, Pub. Philadelphia (1996); Brown et al. (1992) Lancet, 340: 24-27), and the decontamination difficulties (Asher et al. (1986) pages 59-71 In: Laboratory Safety: Principles and Practices, Miller ed. Am. Soc. Microb.), and recent concern about bovine spongiform encephalopathy (British Med. J. 1995; 311: 1415-1421) underlie the urgency of having a diagnostic test that would identify humans and animals with transmissible spongiform encephalopathies.
Definitive premortem diagnosis of these transmissible diseases can only be made histopathologically; however, biopsy of brain tissue is not an ideal method due to risks to animals, patients, and health care personnel. Moreover, lesions can be missed because of the patchy nature of the pathological process.
Measurement of most cerebrospinal fluid (CSF) proteins that have been implicated as pre-mortem markers of Creutzfeldt-Jakob disease have not been very useful diagnostically. These include neuron-specific enolase (NSE) (Jimi et al. (1992) Lancet, 211: 37-46; and Zer et al. (1995) Lancet, 345: 160-9-1610), S-100b protein (Jimi et al., supra), brain-type isozyme of creatine kinase (Jimi et al., supra), GTP binding protein G0 (Jimi et al., supra), ubiquitin (Manaka et al. (1992) Neurosci. Letts. 139: 47-49), and lactic acid (Awerbuch et al. (1985) Internat. J. Neurosci., 42: 1-5).
However, two useful marker proteins, designated proteins 130 and 131, were discovered by two-dimensional electrophoresis (2DE) and silver staining surveys of cerebrospinal fluid (CSF) (see, e.g., Harrington et al. (1986) N. Engl. J. Med., 315: 279-283 and U.S. Pat. No. 4,892,814). These markers were shown to have very high sensitivity (21/21) and specificity (515/520) in the diagnosis of Creutzfeldt-Jacob disease, and this test has been extremely useful in the premortem diagnosis of several difficult cases (see, e.g., Croxson et al. (1988) Neurology 38: 1128-30; Blisard et al. (1990) J. Neurological Sci., 99: 75-81; Marzewski et al., (1988) Neurology, 38: 1131-33; Macario et al. (1991) British Med. J. 302: 1149). The only other disease in which these proteins were found was herpes encephalitis which is easily distinguished on clinical presentation. Testing for these markers, however, has required the two-dimensional electrophoresis (2DE) technique, which is cumbersome and time-consuming. Thus, despite the very high correlation of these marker proteins with the disease, the two-dimensional electrophoresis biochemical test has not become practical for clinical use.